Our laboratory is focused on determining the pathogenesis mechanism(s) of age related macular degeneration (AMD). AMD is a complex disease that involves aging but is mediated by multiple genetic and environmental factors. Formation of lipid deposits in the choriocapillaris and Bruch's membrane is a normal process of aging but may create an environment inductive to lipid oxidation and autoimmunity. There is considerable scientific evidence suggesting that lipid deposits tend to oxidize and the oxidized lipids are not only directly toxic but can illicit powerful immune responses. Thus, we are focusing our research towards understanding lipid transport and oxidation in the retina. Our data suggests that the RPE will uptake lipids from circulating LDL and transport to the inner retina as HDL-like particles. The lipid efflux also seems to be mediated via RPE synthesized lipoproteins and ABC-type transporters. In rats, high doses of circulating oxLDL or LDL containing high amounts of the highly toxic 7-ketocholesterol induces choroidal edema and photoreceptor apoptosis. The retina is the only neural tissue directly exposed to light, and photo oxidation is one of the main processes in the formation of oxidized lipids. Photo oxidation of cholesterol to 7-ketocholesterol usually requires a fluorescent chromophore and our data indicates that A2E is capable of catalyzing this photo oxidation. We are also studying enzymes that hydroxylate (CYP46A1 and CYP27A1) or sulfate (SULT2B1) oxysterols, especially 7-ketocholesterol, into more hydrophilic and less toxic compounds. Another group of enzymes we are studying consists of the methionine sulfoxide reductases (MSRs). These enzymes reverse the effects of methionine oxidation in proteins and thus protect the mitochondria and other organelles from the effects of lipid peroxides. We are in the process of generating MSRA miRNA knockdowns in stably transfected cells and in transgenic rats specifically targeting the RPE.